This application is a 371 of PCT /JP93/00096, filed Jan. 27, 1993.
1. Technical Field
This invention relates to novel methotrexate derivatives, more particularly to novel methotrexate derivatives that are useful as antirheumatic agents.
2. Background Art
Methotrexate had long been used as a therapeutic agent for leukemia but ever since Gubner et al. reported its effectiveness in the treatment of rheumatoid arthritis (RA) and psoriasis in 1951, methotrexate has been used as a therapeutic agent for RA in both Europe and the United States of America. Fairly recently, detailed investigations were conducted on the method of administration and dose of methotrexate to reveal that low-dose methotrexate therapy causes fairly less side effects and yet exhibit excellent efficacy. However, the administration of methotrexate causes various side effects that cannot be ignored, such as hepatopathy and pulmonary fibrosis and, hence, a strong need exists for the advent of drugs that cause lesser side effects without compromise in their efficacy.
The present inventors conducted intensive studies in search for methotrexate derivatives that exceed methotrexate in efficacy as a rheumatism treating agent. The present invention has been accomplished on the basis of these studies.
The present invention provides methotrexate derivatives that are represented by the following general formula (II): 
{where W is a group represented by the general formula: 
[where R1 is a lower alkyl group having 1-4 carbon atoms; R2 is a lower alkyl group having 1-4 carbon atoms or a trifluoromethyl group; R3 is a hydrogen atom, a lower alkyl group having 1-4 carbon atoms or a trifluoromethyl group; R4 is a hydrogen atom or a lower alkyl group having 1-4 carbon atoms; R5 is a group represented by the general formula COOR6 (where R6 is a hydrogen atom or a lower alkyl group having 1-4 carbon atoms) or a group represented by the formula SO3H; and n is an integer of 1-4], or the general formula: 
[where R7 is a lower alkyl group having 1-4 carbon atoms; R8 is a hydrogen atom or a lower alkyl group having 1-4 carbon atoms; R6 is a group represented by the general formula COOR10 (where R10 is a hydrogen atom or a lower alkyl group having 1-4 carbon atoms) or a group represented by the formula SO3H; and m is an integer of 1-4], or the general formula: 
[where R11 is a hydrogen atom or a lower alkyl group having 1-4 carbon atoms; R12 is a hydrogen atom or a lower alkyl group having 1-4 carbon atoms; R13 is a group represented by the general formula COOR14 (where R14 is a hydrogen atom or a lower alkyl group having 1-4 carbon atoms) or a group represented by the formula SO3H; and l is an integer of 1-4], or the general formula: 
[where R15 is a hydrogen atom or a lower alkyl group having 1-4 carbon atoms; R16 is a hydrogen atom or a lower alkyl group having 1-4 carbon atoms; and k is an integer of 2 or 3].
The present invention also relates to the use of these compounds as antirheumatics. The antirheumatics of the present invention include a known compound, namely, 3xe2x80x2-methylaminopterin (see Cancer Research, Vol. 20, No. 10, 698-733, 1960); however, the use of this compound as an antirheumatic agent has not been known.